Abstract
A 48-year-old woman with HIV infection developed Cushingoid features while she was taking ritonavir-boosted darunavir. Cushing's syndrome was confirmed due to the drug interaction between ritonavir and budesonide. Diagnosis of iatrogenic Cushing's syndrome in HIV-positive patients who are on ritonavir-boosted protease inhibitors (PIs) presents a clinical challenge due to similar clinical features of lipohypertrophy related to ritonavir-boosted PIs. Although this complication has been widely described with the use of inhaled fluticasone, the interaction with inhaled budesonide at therapeutic dose is not widely recognized.
Keywords
Oral glucocorticoid steroids are well known to cause Cushing's syndrome with hypothalamic-pituitary-adrenal (HPA) axis suppression. It is widely believed that inhaled corticosteroids at therapeutic doses are safe and less likely to cause systemic adverse effects. However, with the introduction of new delivery devices and with new potent inhaled corticosteroids, development of Cushing's syndrome with HPA axis suppression has been increasingly reported. 1 Development of Cushing's syndrome with HPA axis suppression at recommended licensed doses of inhaled budesonide (320 μg/day) due to a drug-drug interaction has also been reported in a 37-year-old asthmatic African woman with HIV infection. 2 We confirm the occurrence of this phenomenon in the present case report.
A 48-year-old Caucasian woman was hospitalized in August 2011 because of progressive dyspnoea on exertion of three weeks’ duration. She did not have any cough or pleuritic chest pain. She was known to have asthma for 10 years and had been taking inhaled budesonide 400 μg/formoterol 12 μg (Symbicort 400/12 Turbohaler®) two puffs twice daily for the past 18 months. Her general practitioner diagnosed worsening of asthma and prescribed oral montelukast two weeks prior to her admission. She had been taking ritonavir-boosted darunavir, emtricitabine and efavirenz for the past three years for her chronic HIV infection. Her recent CD4 count was 812 cells/mm3 and the HIV RNA level was undetectable.
In the past, she had been transfused 56 units of blood following a road traffic accident that resulted in liver trauma in 1983. Pneumocystis jiroveci pneumonia was diagnosed along with HIV infection in 1995. She was investigated for Cushing's syndrome in 1996. At the time she was on ritonavir-boosted indinavir but not on any inhaled or oral corticosteroids. The serum evening Cortisol and 24-hour urinary free Cortisol levels were normal and both plasma and urinary Cortisol levels were suppressed satisfactorily with dexamethasone. The Cushingoid appearance (buffalo hump, truncal obesity with purple abdominal striae) was thus attributed to indinavir-related lipohypertrophy.
On examination in August 2011, she was afebrile, blood pressure 140/80, pulse 112/minute. Her respiratory rate was 22/minute at rest. Oxygen saturation on room air was 90%. Auscultation of her lungs was clear and the rest of the physical examination was normal. The chest radiograph was normal and an ECG showed sinus tachycardia with S1Q3T3 abnormality. The computerized tomography pulmonary angiogram confirmed bilateral extensive pulmonary emboli. Thrombophilia screening including protein S, C and anticardiolipin antibodies was normal.
The patient had an extensive painless contusion at the site of subcutaneous injection of enoxaparin on admission while her international normalized ratio and platelets were normal. It was noted that she had experienced worsening of her Cushingoid habitus over the past two years (buffalo hump, weight gain, truncal obesity with abdominal purple striae), which prompted a check of her serum Cortisol. Morning serum Cortisol was less than 30 nmol/L. A tetracosactide (synacthen test) stimulation test showed marked suppression of the HPA axis, with a basal Cortisol of 40 nmol/L, only rising to 136 nmol/L at 30 minutes and 165 nmol/L at 60 minutes (normal >550 nmol/L). Urea, electrolytes and blood glucose were normal. Other markers of pituitary function tests such as prolactin, follicle-stimulating hormone, luteinizing hormone and thyroid function were normal. The morning adenocorticotropic hormone concentration was less than <10 ng/L (normal range <51 ng/L).
These tests confirmed iatrogenic Cushing's syndrome with adrenocortical suppression, likely due to inhaled budesonide. She was advised to reduce inhaled steroids to one puff twice daily with a view to discontinuation in the future and educated of the need for steroid replacement during severe intercurrent infections, surgery or trauma and given a hydrocortisone emergency pack with a steroid card. She managed to discontinue inhaled budesonide without requiring any oral hydrocortisone after two weeks. Ritonavir-boosted darunavir was replaced with the integrase inhibitor, raltegravir, which has no anticipated drug-drug interactions with corticosteroids.
She was reviewed in October 2011. Morning serum Cortisol was 240 nmol/L and Synacthen® test was normal (60 minutes Cortisol was 650 nmol/L). Nonetheless, her phenotypic Cushingoid features remained unchanged.
Discussion
Asthma is a very common disease and inhaled corticosteroids are widely used. At the same time the prevalence of HIV infection has risen worldwide due to improved survival as a result of combination antiretroviral therapy. It is therefore inevitable to observe both conditions occurring in the same patient, as in our case. It is generally believed that inhaled corticosteroids have fewer adverse effects compared with oral corticosteroids. 3 However, with the introduction of new delivery devices and of new potent corticosteroids, the development of Cushing's syndrome with HPA axis suppression due to inhaled steroids had increasingly been reported 4 Cushing's syndrome with HPA axis suppression has also been reported with dexamethasone eye drops in a patient treated with ritonavir-boosted atazanavir. 5
Cushing's syndrome with adrenal suppression secondary to ritonavir and fluticasone co-administration has been widely described in comparison to the same occurrence with budesonide. This is because fluticasone has a long half-life and is 300 times more lipophilic than budesonide. These factors contribute to increased concentration of fluticasone and more frequent suppression of the HPA axis compared with other inhaled corticosteroids. 6
Our patient developed Cushingoid features with HPA axis suppression and with low concentrations of serum Cortisol when she was prescribed recommended licensed doses of inhaled budesonide (1600 μg/day). Budesonide is metabolized by hepatic CYP3A4 and the P-glycoprotein (PGP) export pump, which helps to excrete CYP3A4 substrates via the gastrointestinal tract. Protein inhibitors (PIs) such as ritonavir and darunavir inhibit CYP3A4 and PGP and result in increased serum concentrations of corticosteroids. 7 The drug interaction probability scale score characterized this as a probable drug interaction. 8
Our patient was prescribed inhaled corticosteroids for worsening of asthma by her general practitioner; unfortunately this was overlooked at her regular HIV clinic follow-up, which is located in a hospital setting. This drug-drug interaction is of growing concern at and warrants more proactive assessment in the HIV clinic setting in order to detect the problem before significant symptoms arise. In addition, all pre-scribers should be aware of the potential for inhaled corticosteroids to interact with ritonavir-boosted regimens, and alternatives should be considered before prescribing these agents concurrently.
Physicians should be made aware that therapeutic dose of inhaled corticosteroids can potentially cause Cushing's syndrome with low levels of serum Cortisol and should alert to the possibility of adrenal crisis. 9 It is particularly important in HIV-positive patients taking ritonavir-boosted PIs, which can significantly increase serum concentrations of corticosteroids. This case has changed our practice by the introduction of a systematic checklist and directly inquiring with HIV clinic patients about all drugs, including inhaled, herbal products and over-the-counter medicines during our routine follow-up appointments.